Nancy Joseph-Ridge

Effects of febuxostat versus allopurinol and placebo in reducing serum urate in subjects with hyperuricemia and gout: A 28‐week, phase III, randomized, double‐blind, parallel‐group trial

OBJECTIVE To compare the urate-lowering efficacy and safety of febuxostat, allopurinol, and placebo in a large group of subjects with hyperuricemia and gout, including persons with impaired renal function. METHODS Subjects (n = 1,072) with hyperuricemia (serum urate level > or = 8.0 mg/dl) and gout with normal or impaired (serum creatinine level >1.5 to < or = 2.0 mg/dl) renal function were randomized to receive once-daily febuxostat (80 mg, 120 mg, or 240 mg), allopurinol (300 or 100 mg, based on renal function), or placebo for 28 weeks. RESULTS Significantly (P < or = 0.05) higher percentages of subjects treated with febuxostat 80 mg (48%), 120 mg (65%), and 240 mg (69%) attained the primary end point of last 3 monthly serum urate levels <6.0 mg/dl compared with allopurinol (22%) and placebo (0%). A significantly (P < 0.05) higher percentage of subjects with impaired renal function treated with febuxostat 80 mg (4 [44%] of 9), 120 mg (5 [45%] of 11), and 240 mg (3 [60%] of 5) achieved the primary end point compared with those treated with 100 mg of allopurinol (0 [0%] of 10). Proportions of subjects experiencing any adverse event or serious adverse event were similar across groups, although diarrhea and dizziness were more frequent in the febuxostat 240 mg group. The primary reasons for withdrawal were similar across groups except for gout flares, which were more frequent with febuxostat than with allopurinol. CONCLUSION At all doses studied, febuxostat more effectively lowered and maintained serum urate levels <6.0 mg/dl than did allopurinol (300 or 100 mg) or placebo in subjects with hyperuricemia and gout, including those with mild to moderately impaired renal function.

Febuxostat (TMX-67), a novel, non-purine, selective inhibitor of xanthine oxidase, is safe and decreases serum urate in healthy volunteers.

In order to evaluate the safety, pharmacological properties, and urate‐lowering efficacy of febuxostat, a non‐purine, selective inhibitor of xanthine oxidase, a Phase 1, 2‐week, multiple‐dose, placebo‐controlled, dose‐escalation study was conducted in 154 healthy adults of both sexes. Daily febuxostat doses in the range 10 mg to 120 mg resulted in proportional mean serum urate reductions ranging from 25% to 70% and in proportional increases in maximum febuxostat plasma concentrations and area under plasma concentration versus time curves. Accompanying the hypouricemic effect were increases in serum xanthine concentrations, decreases in urinary uric acid excretion, and increases in urinary xanthine and hypoxanthine excretion, confirming inhibition of xanthine oxidase activity by febuxostat. Hepatic conjugation and oxidative metabolism were the major pathways of elimination of febuxostat from the body, and renal elimination did not appear to play a significant role. Although not uncommon, adverse events were mild and self‐limited, and no deaths or serious adverse events were observed. Febuxostat is a safe and potent hypouricemic agent in healthy humans.

The Effect of Mild and Moderate Hepatic Impairment on Pharmacokinetics, Pharmacodynamics, and Safety of Febuxostat, a Novel Nonpurine Selective Inhibitor of Xanthine Oxidase

To assess the effect of hepatic impairment on the pharmacokinetics, pharmacodynamics, and safety of febuxostat at steady state, multiple once‐daily 80‐mg oral doses of febuxostat were administered to subjects with normal hepatic function and to subjects with mild or moderate hepatic impairment. There were no statistically significant differences in the plasma pharmacokinetic parameters for unbound febuxostat and its active metabolites between subjects with mild or moderate hepatic impairment and those with normal hepatic function. The percentage decrease in serum uric acid appeared to be lower in hepatic impairment groups (49% [mild] and 48% [moderate]) as compared to the normal hepatic group (62%). This lower percentage decrease was minimal and not considered clinically significant. Febuxostat 80 mg once daily appears to be generally safe and well tolerated in mildly and moderately impaired hepatic function groups, and dose adjustment is not required in subjects with mild to moderate hepatic impairment.

Pharmacokinetics, Pharmacodynamics and Safety of Febuxostat, a Non-Purine Selective Inhibitor of Xanthine Oxidase, in a Dose Escalation Study in Healthy Subjects

BackgroundFebuxostat is a novel non-purine selective inhibitor of xanthine oxidase currently being developed for the management of hyperuricemia in patients with gout.ObjectiveTo investigate the pharmacokinetics, pharmacodynamics and safety of febuxostat over a range of oral doses in healthy subjects.MethodsIn a phase I, dose-escalation study, febuxostat was studied in dose groups (10, 20, 30, 40, 50, 70, 90, 120, 160, 180 and 240mg) of 12 subjects each (10 febuxostat plus 2 placebo). In all groups, subjects were confined for 17 days and were administered febuxostat once daily on day 1, and days 3–14. During the course of the study, blood and urine samples were collected to assess the pharmacokinetics of febuxostat and its metabolites, and its pharmacodynamic effects on uric acid, xanthine and hypoxanthine concentrations after both single and multiple dose administration. Safety measurements were also obtained during the study.ResultsOrally administered febuxostat was rapidly absorbed with a median time to reach maximum plasma concentration following drug administration of 0.5–1.3 hours. The pharmacokinetics of febuxostat were not time dependent (day 14 vs day 1) and remained linear within the 10–120mg dose range, with a mean apparent total clearance of 10–12 L/h and an apparent volume of distribution at steady state of 33–64L. The harmonic mean elimination half-life of febuxostat ranged from 1.3 to 15.8 hours. The increase in the area under the plasma concentration-time curve of febuxostat at doses >120mg appeared to be greater than dose proportional, while the febuxostat maximum plasma drug concentration was dose proportional across all the doses studied. Based on the urinary data, febuxostat appeared to be metabolised via glucuronidation (22–14% of the dose) and oxidation (2–8%) with only 1–6% of the dose being excreted unchanged via the kidneys. Febuxostat resulted in significant decreases in serum and urinary uric acid concentrations and increases in serum and urinary xanthine concentrations. The percentage decrease in serum uric acid concentrations ranged from 27% to 76% (net change: 1.34–3.88 mg/dL) for all doses and was dose linear for the 10–120 mg/day dosage range. The majority of adverse events were mild-to-moderate in intensity.ConclusionFebuxostat was well tolerated at once-daily doses of 10–240mg. There appeared to be a linear pharmacokinetic and dose-response (percentage decrease in serum uric acid) relationship for febuxostat dosages within the 10–120mg range. Febuxostat was extensively metabolised and renal function did not seem to play an important role in its elimination from the body.

Determinants of the clinical outcomes of gout during the first year of urate-lowering therapy.

Clinical benefit early in urate-lowering treatment of gout is difficult to document. We examined data from 1,832 gouty subjects treated with either urate-lowering agents or placebo to identify determinants of gout flare incidence and tophus size during year 1 of treatment. Reductions from pretreatment serum urate levels influenced flare frequency and tophus size, but the effect of urate level on flare incidence was biphasic. Lower urate levels were associated with higher flare incidence early in treatment but lower incidence by one year. The complex relationship between urate-lowering and clinical outcome early in treatment has implications for both clinical and investigative approaches to urate-lowering management.

Prevalence of comorbid conditions and prescription medication use among patients with gout and hyperuricemia in a managed care setting.

Background:Comorbid disorders and multiple prescription drug use are common among patients with gout and/or hyperuricemia and may influence the clinical course and outcome of gout. Objective:We wanted to document the conditions and associated medications in a large group of patients with gout in a managed care setting. Methods:This study was a 2-year, retrospective, administrative claims analysis examining comorbid conditions and medication use among managed care enrollees with gout/hyperuricemia across the United States. Results:Of the 9482 study subjects (82.1% men, mean age 52 years), 57.9% had hypertension, 45.3% had a lipid disorder, 32.5% had both conditions, and 19.9% had diabetes mellitus. During the 24-month follow-up period, subjects had 5 ± 3.14 (mean ± standard deviation) different comorbid conditions and filled prescriptions for of 11.0 ± 7.90 different medications. The most commonly filled prescriptions included antihypertensive drugs, 3-hydroxy-3-methylglutaryl-coenzyme A (HMG-CoA) reductase inhibitors (statins), and nonsteroidal antiinflammatory drugs (NSAIDs). Conclusions:The study indicates a high prevalence of both comorbid conditions and multiple medication use among managed care enrollees with gout and/or hyperuricemia. Heightened awareness of these associated disorders is important because they may warrant treatment of their own accord and often some modification of gout management. Drugs, particularly diuretics and prophylactic aspirin, could potentially contribute to the development of hyperuricemia and gout.

The Effect of Age and Gender on Pharmacokinetics, Pharmacodynamics, and Safety of Febuxostat, a Novel Nonpurine Selective Inhibitor of Xanthine Oxidase

Febuxostat is a novel nonpurine selective inhibitor of xanthine oxidase, which is currently being developed for the management of hyperuricemia in patients with gout. The effect of age and gender on the pharmacokinetics, pharmacodynamics, and safety of once‐daily oral febuxostat 80 mg was assessed in healthy male and female subjects after 7 days. Following multiple dosing with febuxostat, there were no statistically significant differences in the plasma or urinary pharmacokinetic or pharmacodynamic parameters between subjects aged 18 to 40 years and ≥65 years. Although unbound peak concentration (Cmax,u) and area under the concentration‐time curve (AUC24,u) for febuxostat were higher in women as compared with men (31.5 vs 23.6 ng/mL, P ≤ .01, and 62.8 vs 53.9 ng·h/mL, P ≤ .05, for Cmax,u and AUC24,u, respectively), the differences were not considered clinically significant and could be largely accounted for by weight differences between male and female subjects. For pharmacodynamic parameters, even though the percentage decrease in serum uric acid 24‐hour mean concentration was slightly greater in women than in men (59% vs 52%, P ≤ .01), this difference was not considered clinically meaningful. Febuxostat was well tolerated in male and female subjects in both age groups. Age or gender had no clinically significant effect on the pharmacokinetics, pharmacodynamics, or safety of febuxostat. Therefore, febuxostat does not require any dose adjustments based on age or gender.

Pharmacokinetic interactions of concomitant administration of febuxostat and NSAIDs.

To evaluate the effect of febuxostat on the pharmacokinetics of indomethacin and naproxen and vice versa, 2 multiple‐dose, 3‐period crossover studies were performed in healthy subjects. In study 1, subjects received febuxostat 80 mg once daily, indomethacin 50 mg twice daily, or both. In study 2, subjects received febuxostat 80 mg, naproxen 500 mg twice daily, or both. Twenty‐four‐hour blood samples were collected on day 5 in study 1 and day 7 in study 2. In study 1, 90% confidence intervals of geometric mean ratios for maximum plasma concentration (Cmax) and area under the curve (AUC) were within the 0.80 to 1.25 no‐effect range for febuxostat and indomethacin. In study 2, 90% confidence intervals for febuxostat Cmax and AUC extended above that range, with increases of 28% and 40% in Cmax and AUC24, respectively. However, 90% confidence intervals for naproxen Cmax and AUC were within the 0.80 to 1.25 range. Febuxostat had no effect on the plasma pharmacokinetics of indomethacin and naproxen. Similarly, indomethacin had no effect on the plasma pharmacokinetics of febuxostat. Although naproxen caused an increase in plasma exposure to febuxostat, this increase is not expected to be clinically significant. Therefore, based on the plasma pharmacokinetic data in healthy subjects, febuxostat may be administered with indomethacin or naproxen with no dose adjustments for febuxostat, indomethacin, or naproxen.

Metabolic syndrome-related conditions among people with and without gout: prevalence and resource use

ABSTRACT Objective: A cohort of employees with gout were compared to those without to evaluate the differences in prevalence of disorders associated with metabolic syndrome (both those considered underlying and those associated with end-stage morbidity and mortality) as well as the cost of annual medical services (AMS) required for treatment of these conditions. Methods: Employees with gout were identified by International Classification of Diseases‑9 (ICD‑9) code during the calendar years of 2001–2004 and compared to propensity-score matched employees without gout using the Human Capital Management Services Research Reference Database. T‑tests were then used to compare prevalence and average AMS of comorbid disorders defined from Agency for Healthcare and Research Quality (AHRQ) diagnostic categories. Results: ‘Hyperlipidemia’, ‘essential hypertension’, and ‘diabetes mellitus without complications’ ranked in the top 10 categories of mean number of AMS for employees with gout using AHRQ specific categories; the values were higher than found for those without gout (all p < 0.0001). ‘Essential hypertension’, ‘hyperlipidemia’, ‘diabetes mellitus without complications’, and ‘coronary atherosclerosis’ showed an approximate 2:1 prevalence ratio for employees with gout over those without ( p ≤ 0.05). Main study limitations include the small number of subjects with gout, retrospective study design, and possible miscoding and/or non-coding of individuals with the studied disorders. Conclusion: These results support the continued need for patients with gout and their clinicians to be aware of the possibility of the increased risk of associated metabolic syndrome and related comorbidities in these individuals, emphasizing the need for prevention when possible and treatment when necessary.

Effect of febuxostat on pharmacokinetics of desipramine, a CYP2D6 substrate, in healthy subjects

Febuxostat is a novel non‐purine selective inhibitor of xanthine oxidase (NP‐SIXO) being developed for the management of hyperuricemia in patients with gout.